The biphosphonic acids derivatives are an important class of medicaments useful in the treatment of bone disorders such as Paget's disease and osteoporosis.
The bisphosphonic acids derivatives bisphosphonic acid derivatives or pharmaceutical acceptable salts thereof, having structural formula (I),
wherein M1, M2, M3, M4 represents H or a monovalent cation.wherein R represents group as mentioned hereinbelow

The synthesis of 1-hydroxy-1,1-biphosphonic acids are based on reacting a carboxylic acid with a mixture of phosphorous acid and phosphorous halides such as PCl3, PCl5, POCl3, then quenching the reaction mixture with water or a nonoxidizing aqueous acid, followed by heating to hydrolyze the phosphorous intermediates to final product.
U.S. Pat. No. 4,621,077, which relates to the preparation of alendronic acid and neridronic acid, describes the preparation by treating carboxylic acid with a phosphonation reactant in the presence of chlorobenzene, followed by hydrolysis of the reaction mixture by the addition of concentrated hydrochloric acid and subsequent heating of said mixture. The said patent describes the use of three phosphonation mixtures: H3PO3/PCl3, H3PO3/PCl5 and H3PO3/POCl3. The application of this technique leads to obtaining solid and unstirrable masses in the course of the reaction. It is little difficult to adapt these processes to an industrial scale up, since the reaction mixture of the phosphonation step is not homogenous and tends to solidify, preventing stirring, and also the yields obtained are not consistent. Under these conditions, the subsequent hydrolysis step entails substantial risk, due to the presence of small drops of PCl3 occluded in the reaction mixture and which may cause local overheating on contact with the hydrolyzing agent and also explosion of the gases generated.
A series of other patents i.e. U.S. Pat. Nos. 4,407,761, 4,327,039, 4,304,734, 4,267,108, 4,054,598 envisages the use of chlorobenzene as reaction solvent, but also in these cases the drawback described above is again met with.
U.S. Pat. Nos. 4,922,007, 5,019,651 and 5,510,517, as well as J. Org. Chem. 60, 8310, (1995), envisage the use of methanesulphonic acid as reaction solvent. This makes it possible to obtain stirrable masses in the course of the reaction. However, this technique, as reported in J. Org. Chem. 60, 8310, (1995), involves risks of safety in that this solvent gives rise to uncontrollable reactions in the reaction conditions, when the temperature of the reacting mixtures exceeds 85° C.
WO9834940 employs polyalkylene glycols as reaction solvents for synthesizing alendronic acid; however, these solvents have a high cost and are difficult to eliminate from the finished product, given their high boiling point.
In WO0049026, starting from a nitrogen-protected derivative of β-aminopropionic acid to prevent the known problems of stirrability of the reaction mixture, use is made of orthophosphoric acid as the reaction means. The derivatization of the starting product in any case renders the method of synthesis unwieldy and involves the need for introducing additional steps for protection and deprotection.
U.S. Pat. No. 5,792,885 synthesizes pamidronic acid starting from a nitrogen-protected derivative of γ-aminobutyric acid, in aromatic hydrocarbons as the reaction solvents. This method presents the same drawbacks illustrated for the method described in WO0049026.
WO0110874 regards the use of methanesulphonic anhydride as the solvent for producing alendronic acid, but the high cost of the solvent makes the process commercially less attractive.
The complexity and high cost of the prior art procedures has created a need for an improved process for the preparation of bisphosphonic acid or salts. The present invention provides a solution to the problem presented by the prior art.
Surprisingly, present inventors have found that when the reaction is carried out in the presence of diphenyl ether, operationally simple and easily adaptable at an industrial scale.